Intranasal Zinc Remediates Daily Activity Deficits Following Stress and Traumatic Brain Injury



Doherty, Erin N

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Mild traumatic brain injury (mTBI) has become the “signature wound” of the military population in recent combat operations. Repeated mTBI (rmTBI) produces long-term cognitive and behavioral deficits, including irregular circadian rhythm (CR). This can be exacerbated by the high-stress environment experienced by service members. This study employed a mouse model to examine the behavioral effects of rmTBI with chronic variable stress (CVS) on daily circadian activity. In addition, we tested the hypothesis that rmTBI + CVS effects would be ameliorated by supplemental zinc, a biometal that is known to be reduced in the brain following head trauma. Six-week old mice received two varied stressors (e.g., food deprivation, physical restraint, ice bath, predator urine) each day for 14 days. Four closed-head mild TBIs were concurrently administered, with each injury immediately followed by either intranasal zinc treatment or a vehicle control (saline solution). Mice underwent behavioral testing that assessed daily activity via 24- hour wheel-running activity for seven days, and by consecutive Morris water maze (MWM) testing for indices of spatial learning and anxiety. A significant interaction was found between stress and zinc in daily activity (F(1.42, 56.82) = 3.610, p = .048). Stressed mice given vehicle treatment showed a significant deficit in wheel-running activity at the beginning of the dark cycle, but when zinc was administered, the deficit was corrected and activity for stressed mice nearly doubled. For non-stressed mice, zinc resulted in decreased wheel-running activity. MWM performance yielded consistent results, as the stressed-zinc group had the greatest number of platform crossings (F(1,39) = 4.207, p = .047) and reduced thigmotaxis (F(1,39) = 3.222, p = .034) compared to all other groups. Together, these findings suggest that zinc reduced behavioral deficits depending on the level of stress experienced with rmTBI, and that zinc may be efficacious under conditions of chronic stress. Additionally, zinc treatment increased TrkB receptor phosphorylation in the hippocampus in rmTBI animals, suggesting a TrkBmediated neuroprotective mechanism for zinc’s effect in stressed mice.



Traumatic brain injury, Zinc, Circadian rhythm, Stress, TBI, Mouse model